Pharmaceutical compositions and methods for treating erectile dysfunction

#The present invention relates to the use of Angiotensin-(1-7), alone or in combination with other therapeutic agents in treating erectile dysfunction (ED). Methods for treating ED and/or to restore erectile capacity are based on the use of Angiotensin-(1-7) alone or in combination with other therapeutic agents are also provided.

#Impotence or erectile insufficiency is a widespread disorder that is thought to affect about twelve percent of adult men under age forty-five, about twenty percent of men at age sixty, and about fifty-five percent of men at age seventy-five. A number of causes of erectile insufficiency, in addition to anatomical deficiencies of the penis or scrotum that preclude an erection sufficient for vaginal penetration, have been identified. These causes are psychological and physical in origin and in any individual suffering from impotence there may be more than one cause of erectile dysfunction.

#Erectile dysfunction can be psychological, resulting, for example, from anxiety or depression, with no apparent somatic or organic impairment. Such erectile dysfunction, which is referred to as “psychogenic”, is responsible for about fifteen to twenty percent of cases of impotence. In other cases, the erectile dysfunction is associated with atherosclerosis of the arteries supplying blood to the penis; such dysfunction is referred to as “arteriogenic” or “atherosclerotic.” About forty to sixty percent of cases of impotence are arteriogenic in origin.

#The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Patent and Trademark Office upon request and payment of the necessary fee.

#FIG. 1 shows the immunolocalization of Mas on human and rat penile structures. Mas was localized in human (a-b) and rat (c-d) cavernosal endothelial (triangles) and smooth muscle cell membranes (arrows), rat arteriolar endothelial and smooth muscle cells (d-e).

#FIG. 2 graphically illustrates the in vivo effect of Ang-(1-7) on rat ganglionic-stimulated erectile response. Ang-(1-7) (a-b) increased the CCP/MAP rise induced by ganglionic stimulation that was blunted by A-779 infusion (c). A-779 reduces CCP/MAP rise induced by minimal stimuli in which the maximal value of the CCP/MAP was observed (d-e). L-NAME attenuated CCP/MAP rise induced by electrical stimulation that was not overcome by Ang(1-7) (f). All results are expressed as mean±s.e.m. Statistical analysis was performed with ANOVA followed by Bonferroni post hoc test. *, P<0.05, ** P<0.01 compared with control, recorded 10 min before drug administration. t Test was performed in the A-779 and L-NAME protocol. * P<0.05 compared with control.

#ED is a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. An increase in ED is often associated with age and is generally caused by a physical disease or as a side-effect of drug treatment. The major medications responsible for ED are anti-hypertensives (e.g., beta-blockers, sympathyolytics, and diuretics), and anti-diabetics.

#ED and vascular disease (e.g., hypertension) are thought to be linked at the level of the endothelium. Endothelial dysfunction results in an inability of the smooth muscle cell lining in the arterioles to relax, thus preventing vasodilation. Nitric oxide (NO) is a potent vasodilator and is secreted by the endothelium, being synthesized from L-arginine by the endothelial enzyme NO synthase (eNOS).

#Ang-(1-7) promotes release of prostaglandins from vascular endothelial and smooth muscle cells, release of NO, vasodilation, inhibition of vascular cell growth and attenuation of Ang II-induced vasoconstriction.